Protein kinase C? is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer.

ABSTRACT: Protein kinase C ? (PKC?) regulates apoptosis in the mammary gland, however, the functional contribution of PKC? to the development or progression of breast cancer has yet to be determined. Meta-analysis of ErbB2-positive breast cancers shows increased PKC? expression, and a negative correlation between PKC? expression and prognosis. Here, we present in-vivo evidence that PKC? is essential for the development of mammary gland tumors in a ErbB2-overexpressing transgenic mouse model, and in-vitro evidence that PKC? is required for proliferative signaling downstream of the ErbB2 receptor. Mouse mammary tumor virus (MMTV)-ErbB2 mice lacking PKC? (?KO) have increased tumor latency compared with MMTV-ErbB2 wild-type (?WT) mice, and the tumors show a dramatic decrease in Ki-67 staining. To explore the relationship between PKC? and ErbB2-driven proliferation more directly, we used MCF-10A cells engineered to express a synthetic ligand-inducible form of the ErbB2 receptor. Depletion of PKC? with short hairpin RNA inhibited ligand-induced growth in both two-dimensional (2D) (plastic) and three-dimensional (3D) (Matrigel) culture, and correlated with decreased phosphorylation of the ErbB2 receptor and reduced activation of Src and MAPK/ERK pathways. Similarly, in human breast cancer cell lines in which ErbB2 is overexpressed, depletion of PKC? suppresses proliferation, Src and ERK activation. PKC? appears to drive proliferation through the formation of an active ErbB2/PKC?/Src signaling complex, as depletion of PKC? disrupts association of Src with the ErbB2 receptor. Taken together, our studies present the first evidence that PKC? is a critical regulator of ErbB2-mediated tumorigenesis, and suggest further investigation of PKC? as a target in ErbB2-positive breast cancer.

SUBMITTER: Allen-Petersen BL 

PROVIDER: S-EPMC4292929 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature